title: Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia.
abstract: Tumor-associated immune suppression can lead to defective T cell-mediated antitumor immunity. Here, we identified a unique phenotype of exhausted T cells in mice with advanced acute myelogenous leukemia (AML). This phenotype is characterized by the coexpression of Tim-3 and PD-1 on CD8(+) T cells in the liver, the major first site of AML metastases. PD-1 and Tim-3 coexpression increased during AML progression. PD-1(+)Tim-3(+) CD8(+) T cells were deficient in their ability to produce IFN-γ, TNF-α, and IL-2 in response to PD-1 ligand (PDL1) and Tim-3 ligand (galectin-9) expressing AML cells. PD-1 knockout (KO), which were partially resistant to AML challenge, up-regulated Tim-3 during AML progression and such Tim-3(+)PD-1- KO CD8(+) T cells had reduced cytokine production. Galectin-9 KO mice were more resistant to AML, which was associated with reduced T-regulatory cell accumulation and a modest induction of PD-1 and Tim-3 expression on CD8(+) T cells. Whereas blocking the PD-1/PDL1 or Tim-3/galectin-9 pathway alone was insufficient to rescue mice from AML lethality, an additive effect was seen in reducing-albeit not eliminating-both tumor burden and lethality when both pathways were blocked. Therefore, combined PD-1/PDL1 and Tim-3/galectin-9 blockade may be beneficial in preventing CD8(+) T-cell exhaustion in patients with hematologic malignancies such as advanced AML.
authors.affiliation: Masonic Cancer Center and Department of Pediatrics, Division of Hematology/Oncology and Blood and Marrow Transplantation, Kagawa University, Kagawa, Japan.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Munger
authors.forename: Rachelle G
authors.initials: RG
authors.lastname: Veenstra
authors.forename: Brenda J
authors.initials: BJ
authors.lastname: Weigel
authors.forename: Mitsuomi
authors.initials: M
authors.lastname: Hirashima
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Ana C
authors.initials: AC
authors.lastname: Anderson
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D037161:Galectins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D005804:Genes, Lethal; D000072597:Hepatitis A Virus Cellular Receptor 2; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D008099:Liver / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D037161:Galectins; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011991:Receptors, Virus; C508186:galectin 9, mouse